miR-192/215-5p Act as Tumor Suppressors and Link Crohn's Disease and Colorectal Cancer by Targeting Metabolic Pathways: A Comprehensive Database Mining and Experimental Study

Abstract Background Candidate markers for Crohn’s Disease (CD) may be identified via gene expression-based construction of metabolic networks (MN). These can computationally describe gene-protein-reaction associations for entire tissues and also predict the flux of reactions (rate of turnover of specific molecules via a metabolic pathway). Recon3D is the most comprehensive human MN to date. We used publicly available CD transcriptomic data along with Recon3D to identify metabolites as potential diagnostic and prognostic biomarkers. Methods Terminal ileal gene expression profiles (36,372 genes; 218 CD. 42 controls) from the RISK cohort (Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn’s Disease) and their transcriptomic abundances were used. Recon3D was pruned to only include RISK dataset transcripts which determined metabolic reaction linkage with transcriptionally active genes. Flux balance analysis (FBA) was then run using RiPTiDe with context specific transcriptomic data to further constrain genes (Figure 1). RiPTiDe was independently run on transcriptomic data from both CD and controls. From the pruned and constricted MN obtained, reactions were extracted for further analysis. Results After applying the necessary constraints to modify Recon3D, 527 CD and 537 control reactions were obtained. Reaction comparison with a publicly available list of healthy small intestinal epithelial reactions (n=1282) showed an overlap of 80 CD and 84 control reactions. These were then further grouped based on their metabolic pathways. RiPTiDe identified context specific metabolic pathway activity without supervision and the percentage of forward, backward, and balanced reactions for each metabolic pathway (Figure 2). The metabolite concentrations in the small intestine was altered among CD patients. Notably, the citric acid cycle and malate-aspartate shuttle were affected, highlighting changes in mitochondrial metabolic pathways. This is illustrated by changes in the number of reactions at equilibrium between CD and control. Conclusions The results are relevant as cytosolic acetyl-CoA is needed for fatty acid synthesis and is obtained by removing citrate from the citric acid cycle. An intermediate removal from the cycle has significant cataplerotic effects. The malate-aspartate shuttle also allows electrons to move across the impermeable membrane in the mitochondria (fatty acid synthesis location). These findings are reported by previously published studies where gene expression for fatty acid synthesis is altered in CD patients along with mitochondrial metabolic pathway changes, resulting in altered cell homeostasis. In-depth analysis is currently underway with our work supporting the utility of potential metabolic biomarkers for CD diagnosis, management and improved care.

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Gut Microbiota and Metabolic Specificity in Ulcerative Colitis and Crohn's Disease

Frontiers in Medicine ◽

10.3389/fmed.2020.606298 ◽

2020 ◽

Vol 7 ◽

Author(s):

Jagadesan Sankarasubramanian ◽

Rizwan Ahmad ◽

Nagavardhini Avuthu ◽

Amar B. Singh ◽

Chittibabu Guda

Keyword(s):

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Gut Microbiota ◽

Gut Microbiome ◽

Metabolic Pathways ◽

Meta Analysis ◽

Metabolic Effects ◽

Taxonomic Rank ◽

Disease Specific

Background: Inflammatory bowel disease (IBD) represents multifactorial chronic inflammatory conditions in the gastrointestinal tract and includes Crohn's disease (CD) and ulcerative colitis (UC). Despite similarities in pathobiology and disease symptoms, UC and CD represent distinct diseases and exhibit diverse therapeutic responses. While studies have now confirmed that IBD is associated with dramatic changes in the gut microbiota, specific changes in the gut microbiome and associated metabolic effects on the host due to CD and UC are less well-understood.Methods: To address this knowledge gap, we performed an extensive unbiased meta-analysis of the gut microbiome data from five different IBD patient cohorts from five different countries using QIIME2, DIAMOND, and STAMP bioinformatics platforms. In-silico profiling of the metabolic pathways and community metabolic modeling were carried out to identify disease-specific association of the metabolic fluxes and signaling pathways.Results: Our results demonstrated a highly conserved gut microbiota community between healthy individuals and IBD patients at higher phylogenetic levels. However, at or below the order level in the taxonomic rank, we found significant disease-specific alterations. Similarly, we identified differential enrichment of the metabolic pathways in CD and UC, which included enriched pathways related to amino acid and glycan biosynthesis and metabolism, in addition to other metabolic pathways.Conclusions: In conclusion, this study highlights the prospects of harnessing the gut microbiota to improve understanding of the etiology of CD and UC and to develop novel prognostic, and therapeutic approaches.

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Effects of oral bovine lactoferrin on a mouse model of inflammation associated colon cancer

Biochemistry and Cell Biology ◽

10.1139/bcb-2020-0087 ◽

2020 ◽

Author(s):

Hajime Tanaka ◽

Sivagami Gunasekaran ◽

Dina Mourad Saleh ◽

William Theodore Alexander ◽

David Bedell Alexander ◽

...

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Mouse Model ◽

Controlled Trial ◽

Disease Patient ◽

Inhibitory Effect ◽

Bovine Lactoferrin ◽

Increased Risk

Both ulcerative colitis and colonic Crohn's disease patients have a significantly increased risk of developing colorectal cancer. bLF is reported to inhibit the development of colon cancer in rats and mice, and in a placebo controlled trial, ingestion of bLF inhibited the growth of intestinal polyps. In addition, in a case study a Crohn's disease patient was reported to have remained in remission for over 7 years while ingesting 1 gram of bLF daily. Thus, bLF has an inhibitory effect on colon carcinogenesis, and it may also promote remission of Crohn's disease. The purpose of the present study was to begin to investigate the effect of bLF on a mouse model of IBD-related colorectal cancer. Azoxymethane (AOM) was used to initiate intestinal cancer and dextran sulfate sodium (DSS) was used to induce IBD-like inflammation in the intestine of C57BL/6 mice. Mice were divided into 4 groups: untreated, bLF alone, AOM+DSS, and AOM+DSS+bLF. At the end of the study, mice given AOM+DSS+LF had a better fecal score, less wounding in the colon, and less weight loss than mice in the AOM+DSS group. However, there were no statistically significant differences between the two groups in tumor burden.

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